Adult Animal Stem Cell-Derived Organoids in Biomedical Research and the One Health Paradigm.

Preclinical biomedical research is limited by the predictiveness of in vivo and in vitro models. While in vivo models offer the most complex system for experimentation, they are also limited by ethical, financial, and experimental constraints. In vitro models are simplified models that do not offer the same complexity as living animals but do offer financial affordability and more experimental freedom; therefore, they are commonly used. Traditional 2D cell lines cannot fully simulate the complexity of the epithelium of healthy organs and limit scientific progress. The One Health Initiative was established to consolidate human, animal, and environmental health while also tackling complex and multifactorial medical problems. Reverse translational research allows for the sharing of knowledge between clinical research in veterinary and human medicine. Recently, organoid technology has been developed to mimic the original organ's epithelial microstructure and function more reliably. While human and murine organoids are available, numerous other organoids have been derived from traditional veterinary animals and exotic species in the last decade. With these additional organoid models, species previously excluded from in vitro research are becoming accessible, therefore unlocking potential translational and reverse translational applications of animals with unique adaptations that overcome common problems in veterinary and human medicine.

Multiomic analysis defines the first microRNA atlas across all small intestinal epithelial lineages and reveals novel markers of almost all major cell types.

MicroRNA-mediated regulation is critical for the proper development and function of the small intestinal (SI) epithelium. However, it is not known which microRNAs are expressed in each of the cell types of the SI epithelium. To bridge this important knowledge gap, we performed comprehensive microRNA profiling in all major cell types of the mouse SI epithelium. We used flow cytometry and fluorescence-activated cell sorting with multiple reporter mouse models to isolate intestinal stem cells, enterocytes, goblet cells, Paneth cells, enteroendocrine cells, tuft cells, and secretory progenitors. We then subjected these cell populations to small RNA-sequencing. The resulting atlas revealed highly enriched microRNA markers for almost every major cell type (https://sethupathy-lab.shinyapps.io/SI_miRNA/). Several of these lineage-enriched microRNAs (LEMs) were observed to be embedded in annotated host genes. We used chromatin-run-on sequencing to determine which of these LEMs are likely cotranscribed with their host genes. We then performed single-cell RNA-sequencing to define the cell type specificity of the host genes and embedded LEMs. We observed that the two most enriched microRNAs in secretory progenitors are miR-1224 and miR-672, the latter of which we found is deleted in hominin species. Finally, using several in vivo models, we established that miR-152 is a Paneth cell-specific microRNA.NEW & NOTEWORTHY In this study, first, microRNA atlas (and searchable web server) across all major small intestinal epithelial cell types is presented. We have demonstrated microRNAs that uniquely mark several lineages, including enteroendocrine and tuft. Identification of a key marker of mouse secretory progenitor cells, miR-672, which we show is deleted in humans. We have used several in vivo models to establish miR-152 as a specific marker of Paneth cells, which are highly understudied in terms of microRNAs.

Inflammation, negative affect, and amyloid burden in Alzheimer's disease: Insights from the kynurenine pathway.

BACKGROUND: Depressive symptoms in Alzheimer's disease (AD) predict worse cognitive and functional outcomes. Both AD and major depression inflammatory processes are characterized by shunted tryptophan metabolism away from serotonin (5-HT) and toward the neuroinflammatory kynurenine (Kyn) pathway. The present study assessed associations between Kyn and behavioral, neuroanatomical, neuropathological, and physiological outcomes common to both AD and negative affect across the AD continuum. METHODS: In 58 cognitively normal, 396 mild cognitive impairment, and 112 AD participants from the Alzheimer's Disease Neuroimaging Initiative-1 (ADNI1) cohort, serum markers of 5-HT, tryptophan, and Kyn were measured and their relationships investigated with immunologic markers, affect and functional outcomes, CSF markers of beta-amyloid (Aß) and tau, and regional gray matter. RESULTS: A higher Kyn/Tryptophan ratio was linked to many inflammatory markers, as well as lower functional independence and memory scores. A higher Kyn/5-HT ratio showed similar associations, but also strong relationships with negative affect and neuropsychiatric disturbance, executive dysfunction, and global cognitive decline. Further, gray matter atrophy was seen in hippocampus, anterior cingulate, and prefrontal cortices, as well as greater amyloid and total tau deposition. Finally, using moderated-mediation, several pro-inflammatory factors partially mediated Kyn/5-HT and negative affect scores in participants with subclinical Aß (i.e., Aß-), whereas such associations were fully mediated by Complement 3 in Aß+ participants. CONCLUSION: These findings suggest that inflammatory signaling cascades may occur during AD, which is associated with increased Kyn metabolism that influences the pathogenesis of negative affect. Aß and the complement system may be critical contributing factors in this process.

Colonic mucosal and serum expression of microRNAs in canine large intestinal inflammatory bowel disease.

BACKGROUND: Canine inflammatory bowel disease (IBD) is a group of chronic gastrointestinal (GI) disorders of still largely unknown etiology. Canine IBD diagnosis is time-consuming and costly as other diseases with similar signs should be initially excluded. In human IBD microRNA (miR) expression changes have been reported in GI mucosa and blood. Thus, there is a possibility that miRs may provide insight into disease pathogenesis, diagnosis and even treatment of canine IBD. The aim of this study was to determine the colonic mucosal and serum relative expression of a miRs panel in dogs with large intestinal IBD and healthy control dogs. RESULTS: Compared to healthy control dogs, dogs with large intestinal IBD showed significantly increased relative expression of miR-16, miR-21, miR-122 and miR-147 in the colonic mucosa and serum, while the relative expression of miR-185, miR-192 and miR-223 was significantly decreased. Relative expression of miR-146a was significantly increased only in the serum of dogs with large intestinal IBD. Furthermore, serum miR-192 and miR-223 relative expression correlated to disease activity and endoscopic score, respectively. CONCLUSION: Our data suggest the existence of dysregulated miRs expression patterns in canine IBD and support the potential future use of serum miRs as useful noninvasive biomarkers.

Derivation of adult canine intestinal organoids for translational research in gastroenterology.

BACKGROUND: Large animal models, such as the dog, are increasingly being used for studying diseases including gastrointestinal (GI) disorders. Dogs share similar environmental, genomic, anatomical, and intestinal physiologic features with humans. To bridge the gap between commonly used animal models, such as rodents, and humans, and expand the translational potential of the dog model, we developed a three-dimensional (3D) canine GI organoid (enteroid and colonoid) system. Organoids have recently gained interest in translational research as this model system better recapitulates the physiological and molecular features of the tissue environment in comparison with two-dimensional cultures. RESULTS: Organoids were derived from tissue of more than 40 healthy dogs and dogs with GI conditions, including inflammatory bowel disease (IBD) and intestinal carcinomas. Adult intestinal stem cells (ISC) were isolated from whole jejunal tissue as well as endoscopically obtained duodenal, ileal, and colonic biopsy samples using an optimized culture protocol. Intestinal organoids were comprehensively characterized using histology, immunohistochemistry, RNA in situ hybridization, and transmission electron microscopy, to determine the extent to which they recapitulated the in vivo tissue characteristics. Physiological relevance of the enteroid system was defined using functional assays such as optical metabolic imaging (OMI), the cystic fibrosis transmembrane conductance regulator (CFTR) function assay, and Exosome-Like Vesicles (EV) uptake assay, as a basis for wider applications of this technology in basic, preclinical and translational GI research. We have furthermore created a collection of cryopreserved organoids to facilitate future research. CONCLUSIONS: We establish the canine GI organoid systems as a model to study naturally occurring intestinal diseases in dogs and humans, and that can be used for toxicology studies, for analysis of host-pathogen interactions, and for other translational applications.

Correlating Gastrointestinal Histopathologic Changes to Clinical Disease Activity in Dogs With Idiopathic Inflammatory Bowel Disease.

Prior studies have failed to detect a convincing association between histologic lesions of inflammation and clinical activity in dogs with inflammatory bowel disease (IBD). We hypothesized that use of a simplified histopathologic scoring system would improve the consistency of interpretation among pathologists when describing histologic lesions of gastrointestinal inflammation. Our aim was to evaluate the correlation of histopathologic changes to clinical activity in dogs with IBD using this new system. Forty-two dogs with IBD and 19 healthy control dogs were enrolled in this retrospective study. Endoscopic biopsies from the stomach, duodenum, ileum, and colon were independently scored by 8 pathologists. Clinical disease activity was scored using the Canine Inflammatory Bowel Disease Activity Index (CIBDAI) or the Canine Chronic Enteropathy Clinical Activity Index (CCECAI), depending on the individual study center. Summative histopathological scores and clinical activity were calculated for each tissue (stomach, duodenum, ileum, and colon) and each tissue histologic score (inflammatory/morphologic feature). The correlation between CCECAI/CIBDAI and summative histopathologic score was significant ( P < .05) for duodenum ( r = 0.42) and colon ( r = 0.33). In evaluating the relationship between histopathologic scores and clinical activity, significant ( P < .05) correlations were observed for crypt dilation ( r = 0.42), lamina propria (LP) lymphocytes ( r = 0.40), LP neutrophils ( r = 0.45), mucosal fibrosis ( r = 0.47), lacteal dilation ( r = 0.39), and villus stunting ( r = 0.43). Compared to earlier grading schemes, the simplified scoring system shows improved utility in correlating histopathologic features (both summative histology scores and select histologic scores) to IBD clinical activity.

Oral chondroitin sulfate and prebiotics for the treatment of canine Inflammatory Bowel Disease: a randomized, controlled clinical trial.

BACKGROUND: Canine inflammatory bowel disease (IBD) is a chronic enteropathy of unknown etiology, although microbiome dysbiosis, genetic susceptibility, and dietary and/or environmental factors are hypothesized to be involved in its pathogenesis. Since some of the current therapies are associated with severe side effects, novel therapeutic modalities are needed. A new oral supplement for long-term management of canine IBD containing chondroitin sulfate (CS) and prebiotics (resistant starch, ß-glucans and mannaoligosaccharides) was developed to target intestinal inflammation and oxidative stress, and restore normobiosis, without exhibiting any side effects. This double-blinded, randomized, placebo-controlled trial in dogs with IBD aims to evaluate the effects of 180 days administration of this supplement together with a hydrolyzed diet on clinical signs, intestinal histology, gut microbiota, and serum biomarkers of inflammation and oxidative stress. RESULTS: Twenty-seven client-owned biopsy-confirmed IBD dogs were included in the study, switched to the same hydrolyzed diet and classified into one of two groups: supplement and placebo. Initially, there were no significant differences between groups (p > 0.05) for any of the studied parameters. Final data analysis (supplement: n = 9; placebo: n = 10) showed a significant decrease in canine IBD activity index (CIBDAI) score in both groups after treatment (p < 0.001). After treatment, a significant decrease (1.53-fold; p < 0.01) in histologic score was seen only in the supplement group. When groups were compared, the supplement group showed significantly higher serum cholesterol (p < 0.05) and paraoxonase-1 (PON1) levels after 60 days of treatment (p < 0.01), and the placebo group showed significantly reduced serum total antioxidant capacity (TAC) levels after 120 days (p < 0.05). No significant differences were found between groups at any time point for CIBDAI, WSAVA histologic score and fecal microbiota evaluated by PCR-restriction fragment length polymorphism (PCR-RFLP). No side effects were reported in any group. CONCLUSIONS: The combined administration of the supplement with hydrolyzed diet over 180 days was safe and induced improvements in selected serum biomarkers, possibly suggesting a reduction in disease activity. This study was likely underpowered, therefore larger studies are warranted in order to demonstrate a supplemental effect to dietary treatment of this supplement on intestinal histology and CIBDAI.

Novel fused tetrathiocines as antivirals that target the nucleocapsid zinc finger containing protein of the feline immunodeficiency virus (FIV) as a model of HIV infection.

A novel series of fused tetrathiocines were prepared for evaluation of activity against the nucleocapsid protein of the feline immunodeficiency virus (FIV) in an in vitro cell culture approach. The results demonstrated that the compounds display potent nanomolar activity and low toxicity against this key model of HIV infection.

Evaluation of the antiviral efficacy of bis[1,2]dithiolo[1,4]thiazines and bis[1,2]dithiolopyrrole derivatives against the nucelocapsid protein of the Feline Immunodeficiency Virus (FIV) as a model for HIV infection.

A diverse library of bis[1,2]dithiolo[1,4]thiazines and bis[1,2]dithiolopyrrole derivatives were prepared for evaluation of activity against the nucleocapsid protein of the Feline Immunodeficiency Virus (FIV) as a model for HIV, using an in vitro cell culture approach, yielding nanomolar active compounds with low toxicity.

Pharmacokinetics of isavuconazonium sulfate and its active metabolite isavuconazole in healthy dogs.

Invasive fungal infections (IFIs) are growing in importance in veterinary and human medicine. IFIs such as aspergillosis, blastomycosis, coccidioidomycosis and histoplasmosis remain challenging to treat in dogs. Isavuconazole is a novel antifungal medication that, when compared to currently used azoles, has an expanded spectrum of antifungal activity Rudramurthy (2011), Pfaller (2013), Spec (2018), has more predictable pharmacokinetics in humans Desai (2016), Cojutti (2021) and may cause fewer side effects such as liver and renal toxicity Maertens (2016), DiPippo (2018). The pharmacokinetic profile and safety of isavuconazole in dogs has not yet been characterized. The purpose of this study was to evaluate the pharmacokinetics of isavuconazole in healthy dogs that received a single dose of the prodrug isavuconazonium sulfate. Using full crossover design, six healthy beagle dogs received isavuconazonium sulfate at a mean (+/- SD) dose of 20.6 (+/- 2.8) mg/kg orally and 21.8 (+/- 4.2) mg/kg intravenously. Plasma was collected for batched pharmacokinetic analysis of prodrug and metabolite, isavuconazole, by ultra-high-pressure liquid chromatography tandem mass spectrometry (UHPLC-MS/MS). The median (Q1-Q3) maximum isavuconazole peak plasma concentration was estimated at 3,876.5 (2,811.0-4,800.0) ng/mL following oral administration, with a median (Q1-Q3) peak level at 1.3 (1.0-2.0) hours. Following intravenous administration, the median (Q1-Q3) isavuconazole peak plasma concentration was estimated at 3,221.5 (2,241.5-3,609.0) ng/mL, with a median (Q1-Q3) peak level at 0.4 (0.3-0.6) hours. The median (Q1-Q3) half-life of isavuconazole was 9.4 (7.0-12.2) hours and 14.0 (8.1-21.7) hours for oral and intravenous routes, respectively. One dog received inadvertent subcutaneous drug administration without any apparent adverse effects. Another dog experienced an anaphylactic reaction following accidental rapid drug infusion. No other drug-related adverse events were observed. At dosages used in this study, healthy dogs achieved isavuconazole plasma levels comparable to human therapeutic targets, and when properly administered the drug was well-tolerated.

Systemic absorption and gastrointestinal adverse effects from topical ketorolac and diclofenac ophthalmic solutions in healthy dogs.

OBJECTIVE: To investigate systemic absorption and gastrointestinal (GI) adverse effects of topical ketorolac 0.5% and diclofenac 0.1% ophthalmic solutions. ANIMALS: 11 healthy purpose-bred Beagles. METHODS: Dogs were randomly assigned to receive either ketorolac (n = 6) or diclofenac (5), 1 drop in both eyes 4 times daily for 28 days. Upper GI endoscopy was performed on days 0 and 29 with mucosal lesion scores (0 to 7) assigned to each region evaluated. Plasma samples were collected on days 14, 21, and 28 for measurement of diclofenac and ketorolac using high-performance liquid chromatography-mass spectrometry. RESULTS: GI erosions and/or ulcers developed in all ketorolac-treated dogs and 1 of 5 diclofenac-treated dogs. Post-treatment mucosal lesion score for the antrum was higher in the ketorolac group than in the diclofenac group (P = .006) but not significantly different for any other region. Post-treatment antral mucosal lesion scores were significantly related to plasma ketorolac concentrations (P < .001). Ketorolac and diclofenac were detected in the plasma at all time points (median ketorolac day 14, 191 ng/mL; day 21, 173.5 ng/mL; and day 28, 179.5 ng/mL; and median diclofenac day 14, 21.1 ng/mL; day 21, 20.6 ng/mL; day 28, 27.5 ng/mL). Vomiting and decreased appetite events were observed uncommonly and were not significantly different between treatment groups. CLINICAL RELEVANCE: GI ulceration and erosion developed after ophthalmic administration of ketorolac and diclofenac, with higher plasma concentrations and more severe GI lesions associated with ketorolac. Clients should be alerted to this potential risk with ophthalmic use and informed to watch for systemic clinical signs that would warrant veterinary reevaluation.

A machine learning approach for potential Super-Agers identification using neuronal functional connectivity networks.

INTRODUCTION: Aging is often associated with cognitive decline. Understanding neural factors that distinguish adults in midlife with superior cognitive abilities (Positive-Agers) may offer insight into how the aging brain achieves resilience. The goals of this study are to (1) introduce an optimal labeling mechanism to distinguish between Positive-Agers and Cognitive Decliners, and (2) identify Positive-Agers using neuronal functional connectivity networks data and demographics. METHODS: In this study, principal component analysis initially created latent cognitive trajectories groups. A hybrid algorithm of machine learning and optimization was then designed to predict latent groups using neuronal functional connectivity networks derived from resting state functional magnetic resonance imaging. Specifically, the Optimal Labeling with Bayesian Optimization (OLBO) algorithm used an unsupervised approach, iterating a logistic regression function with Bayesian posterior updating. This study encompassed 6369 adults from the UK Biobank cohort. RESULTS: OLBO outperformed baseline models, achieving an area under the curve of 88% when distinguishing between Positive-Agers and cognitive decliners. DISCUSSION: OLBO may be a novel algorithm that distinguishes cognitive trajectories with a high degree of accuracy in cognitively unimpaired adults. Highlights: Design an algorithm to distinguish between a Positive-Ager and a Cognitive-Decliner.Introduce a mathematical definition for cognitive classes based on cognitive tests.Accurate Positive-Ager identification using rsfMRI and demographic data (AUC = 0.88).Posterior default mode network has the highest impact on Positive-Aging odds ratio.

Evaluation of different media compositions promoting hepatocyte differentiation in the canine liver organoid model.

Organoids are 3-dimensional (3D) self-assembled structures capable of replicating the microanatomy and physiology of the epithelial components of their organ of origin. Adult stem cell (ASC) derived organoids from the liver have previously been shown to differentiate into primarily mature cholangiocytes, and their partial differentiation into functional hepatocytes can be promoted using specific media compositions. While full morphological differentiation of mature hepatocytes from ASCs has not yet been reported for any species, the functional differentiation can be approximated using various media compositions. Six differentiation media formulations from published studies on hepatic organoids were used for the differentiation protocol. Target species for these protocols were humans, mice, cats, and dogs, and encompassed various combinations and concentrations of four major hepatocyte media components: Bone morphogenetic protein 7 (BMP7), Fibroblast Growth Factor 19 (FGF19), Dexamethasone (Dex), and Gamma-Secretase Inhibitor IX (DAPT). Additionally, removing R-spondin from basic organoid media has previously been shown to drive the differentiation of ASC into mature hepatocytes. Differentiation media (N = 20) were designed to encompass combinations of the four major hepatocyte media components. The preferred differentiation of ASC-derived organoids from liver tissue into mature hepatocytes over cholangiocytes was confirmed by albumin production in the culture supernatant. Out of the twenty media compositions tested, six media resulted in the production of the highest amounts of albumin in the supernatant of the organoids. The cell lines cultured using these six media were further characterized via histological staining, transmission electron microscopy, RNA in situ hybridization, analysis of gene expression patterns, immunofluorescence, and label-free proteomics. The results indicate that preferential hepatocyte maturation from canine ADC-derived organoids from liver tissue is mainly driven by Dexamethasone and DAPT components. FGF19 did not enhance organoid differentiation but improved cell culture survival. Furthermore, we confirm that removing R-spondin from the media is crucial for establishing mature hepatic organoid cultures.

Establishment and characterization of turtle liver organoids provides a potential model to decode their unique adaptations.

Painted turtles are remarkable for their freeze tolerance and supercooling ability along with their associated resilience to hypoxia/anoxia and oxidative stress, rendering them an ideal biomedical model for hypoxia-induced injuries (including strokes), tissue cooling during surgeries, and organ cryopreservation. Yet, such research is hindered by their seasonal reproduction and slow maturation. Here we developed and characterized adult stem cell-derived turtle liver organoids (3D self-assembled in vitro structures) from painted, snapping, and spiny softshell turtles spanning ~175My of evolution, with a subset cryopreserved. This development is, to the best of our knowledge, a first for this vertebrate Order, and complements the only other non-avian reptile organoids from snake venom glands. Preliminary characterization, including morphological, transcriptomic, and proteomic analyses, revealed organoids enriched in cholangiocytes. Deriving organoids from distant turtles and life stages demonstrates that our techniques are broadly applicable to chelonians, permitting the development of functional genomic tools currently lacking in herpetological research. Such platform could potentially support studies including genome-to-phenome mapping, gene function, genome architecture, and adaptive responses to climate change, with implications for ecological, evolutionary, and biomedical research.

Preclinical modeling of metabolic syndrome to study the pleiotropic effects of novel antidiabetic therapy independent of obesity.

Cardiovascular-kidney-metabolic health reflects the interactions between metabolic risk factors, chronic kidney disease, and the cardiovascular system. A growing body of literature suggests that metabolic syndrome (MetS) in individuals of normal weight is associated with a high prevalence of cardiovascular diseases and an increased mortality. The aim of this study was to establish a non-invasive preclinical model of MetS in support of future research focusing on the effects of novel antidiabetic therapies beyond glucose reduction, independent of obesity. Eighteen healthy adult Beagle dogs were fed an isocaloric Western diet (WD) for ten weeks. Biospecimens were collected at baseline (BAS1) and after ten weeks of WD feeding (BAS2) for measurement of blood pressure (BP), serum chemistry, lipoprotein profiling, blood glucose, glucagon, insulin secretion, NT-proBNP, angiotensins, oxidative stress biomarkers, serum, urine, and fecal metabolomics. Differences between BAS1 and BAS2 were analyzed using non-parametric Wilcoxon signed-rank testing. The isocaloric WD model induced significant variations in several markers of MetS, including elevated BP, increased glucose concentrations, and reduced HDL-cholesterol. It also caused an increase in circulating NT-proBNP levels, a decrease in serum bicarbonate, and significant changes in general metabolism, lipids, and biogenic amines. Short-term, isocaloric feeding with a WD in dogs replicated key biological features of MetS while also causing low-grade metabolic acidosis and elevating natriuretic peptides. These findings support the use of the WD canine model for studying the metabolic effects of new antidiabetic therapies independent of obesity.

Effect of the Probiotic Bacillus subtilis DE-CA9TM on Fecal Scores, Serum Oxidative Stress Markers and Fecal and Serum Metabolome in Healthy Dogs.

BACKGROUND: There is increasing interest in the use of Bacillus species as probiotics since their spore-forming ability favors their survival in the acidic gastric environment over other probiotic species. The subsequent germination of B. subtilis to their vegetative form allows for their growth in the small intestine and may increase their beneficial effect on the host. B. subtilis strains have also previously been shown to have beneficial effects in humans and production animals, however, no reports are available so far on their use in companion animals. STUDY DESIGN: The goal of this study was therefore to investigate the daily administration of 1 × 109 cfu DE-CA9TM orally per day versus placebo on health parameters, fecal scores, fecal microbiome, fecal metabolomics, as well as serum metabolomics and oxidative stress markers in ten healthy Beagle dogs in a parallel, randomized, prospective, placebo-controlled design over a period of 45 days. RESULTS: DE-CA9TM decreased the oxidative status compared to controls for advanced oxidation protein products (AOPP), thiobarbituric acid reactive substances (TBARS) and reactive oxygen metabolites (d-ROMS), suggesting an antioxidant effect of the treatment. Fecal metabolomics revealed a significant reduction in metabolites associated with tryptophan metabolism in the DE-CA9TM-treated group. DE-CA9TM also significantly decreased phenylalanine and homocysteine and increased homoserine and threonine levels. Amino acid metabolism was also affected in the serum metabolome, with increased levels of urea and cadaverine, and reductions in N-acetylornithine in DE-CA9TM compared to controls. Similarly, changes in essential amino acids were observed, with a significant increase in tryptophan and lysine levels and a decrease in homocysteine. An increase in serum guanine and deoxyuridine was also detected, with a decrease in beta-alanine in the animals that ingested DE-CA9TM. CONCLUSIONS: Data generated throughout this study suggest that the daily administration of 1 × 109 cfu of DE-CA9TM in healthy Beagle dogs is safe and does not affect markers of general health and fecal scores. Furthermore, DE-CA9TM administration had a potential positive effect on some serum markers of oxidative stress, and protein and lipid metabolism in serum and feces.

Exploring the secrets of super-aging: a UK Biobank study on brain health and cognitive function.

Communities across the globe are faced with a rapidly aging society, where age is the main risk factor for cognitive decline and development of Alzheimer's and related diseases. Despite extensive research, there have been no successful treatments yet. A rare group of individuals called "super-agers" have been noted to thrive with their exceptional ability to maintain a healthy brain and normal cognitive function even in old age. Studying their traits, lifestyles, and environments may provide valuable insight. This study used a data-driven approach to identify potential super-agers among 7121 UK Biobank participants and found that these individuals have the highest total brain volume, best cognitive performance, and lowest functional connectivity. The researchers suggest a novel hypothesis that these super-agers possess enhanced neural processing efficiency that increases with age and introduce a definition of the "neural efficiency index." Furthermore, several other types of aging were identified and significant structural-functional differences were observed between them, highlighting the benefit of research efforts in personalized medicine and precision nutrition.

Bioenergetic and vascular predictors of potential super-ager and cognitive decline trajectories-a UK Biobank Random Forest classification study.

Aging has often been characterized by progressive cognitive decline in memory and especially executive function. Yet some adults, aged 80 years or older, are "super-agers" that exhibit cognitive performance like younger adults. It is unknown if there are adults in mid-life with similar superior cognitive performance ("positive-aging") versus cognitive decline over time and if there are blood biomarkers that can distinguish between these groups. Among 1303 participants in UK Biobank, latent growth curve models classified participants into different cognitive groups based on longitudinal fluid intelligence (FI) scores over 7-9 years. Random Forest (RF) classification was then used to predict cognitive trajectory types using longitudinal predictors including demographic, vascular, bioenergetic, and immune factors. Feature ranking importance and performance metrics of the model were reported. Despite model complexity, we achieved a precision of 77% when determining who would be in the "positive-aging" group (n = 563) vs. cognitive decline group (n = 380). Among the top fifteen features, an equal number were related to either vascular health or cellular bioenergetics but not demographics like age, sex, or socioeconomic status. Sensitivity analyses showed worse model results when combining a cognitive maintainer group (n = 360) with the positive-aging or cognitive decline group. Our results suggest that optimal cognitive aging may not be related to age per se but biological factors that may be amenable to lifestyle or pharmacological changes.

Fecal acute phase proteins in cats with chronic enteropathies.

BACKGROUND: Chronic enteropathies (CE) are common in cats and reliable biomarkers that can distinguish different causes and predict or monitor response to treatment are currently lacking. HYPOTHESIS: To evaluate certain acute phase proteins in feces that could potentially be used as biomarkers in cats with CE. ANIMALS: Twenty-eight cats with either inflammatory bowel disease (IBD; n = 13), food-responsive enteropathy (FRE; n = 3) or small cell gastrointestinal lymphoma (SCGL; n = 12) and 29 healthy control cats were prospectively enrolled. METHODS: Fecal concentrations of haptoglobin, alpha-1-acid-glycoprotein (AGP), pancreatitis-associated protein-1 (PAP-1), ceruloplasmin, and C-reactive protein (CRP) were measured using Spatial Proximity Analyte Reagent Capture Luminescence (SPARCL) immunoassays before and after initiation of treatment. Cats were treated with diet and/or prednisolone (IBD cats), plus chlorambucil (SCGL cats). RESULTS: Compared with controls, median fecal AGP concentrations were significantly lower (25.1 vs 1.8 µg/g; P = .003) and median fecal haptoglobin (0.17 vs 0.5 µg/g), PAP-1 (0.04 vs 0.4 µg/g) and ceruloplasmin (0.15 vs 4.2 µg/g) concentrations were significantly higher (P < .001) in cats with CE. Median fecal AGP concentrations were significantly lower (P = .01) in cats with IBD and FRE (0.6 µg/g) compared with cats with SCGL (10.75 µg/g). A significant reduction was found in CE cats after treatment for median fecal ceruloplasmin concentrations (6.36 vs 1.16 µg/g; P = .04). CONCLUSIONS: Fecal AGP concentration shows promise to differentiate cats with SCGL from cats with IBD and FRE. Fecal ceruloplasmin concentrations may be useful to objectively monitor response to treatment in cats with CE.